Parenteral infections (as distinct from infections of the gastrointestinal tract) occur when an organism gets access to inter-cellular and intra-cellular components underneath the outer-protective membranes or the skin. Punctures, injections, bites, cuts, wounds, surgery, splits between skin and mucous membranes are all examples which lead to parenteral infection. Parenteral infection does not include infections within the lumen of the gastro-intestinal tract.
Parenteral infections, particularly bacterial infection via a parenteral route, can lead to serious and life threatening disease with inflammatory response. If not controlled, parenteral infection can lead to sepsis with loss of blood-pressure, putting a subject at risk of a life threatening level of infection.
The most common origins that develop into sepsis are infections of the blood (bacteremia), meninges, lungs, urinary tract, sinuses, skin, wounds, abscesses and surgical procedures. Studies of common causative organisms associated with sepsis show that about 53% of cases are associated with gram-positive bacteria and about 42% with gram-negative bacteria.
Examples of gram-negative bacteria implicated in the development of sepsis include Proteus spp, Serratia spp, Pseudomonas aeruginosa, Neisseria meningitidis, Escherichia coli, Klebsiella pneumoniae. Examples of gram-positives implicated include Staphylococcus aureus, coagulase-negative Staphylococcus spp, Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus spp.
Routinely, sepsis and/or inter-related bacteremia are treated either preventatively (prophylactively) and/or curatively by antibiotics; a well-recognised statistic is that probability of life-survival recedes 6% for each hour-delay in treatment. However, identifying the bacteria at the root of the problem can take days—and even then the antibiotics used don't always work. Antibiotic resistance is leading to further increases in the risk of sepsis and this risk is often exacerbated in hospitals where antibiotic resistance can be particularly high due to the prevalence of the use of antibiotics.
About 30% of the people diagnosed with sepsis die, which makes it one of the leading causes of death in the intensive care unit of most hospitals. It kills approximately 120,000-200,000 people annually in the United States. World-wide, 13 million people develop sepsis each year, and as many as 4 million people die as a result.
The increasing threat of antibiotic-resistant bacteria to the world's population is recognized universally.
The threat is more critical when the infection is caused by an antibiotic-resistant bacterium (“super-bug”). There is an urgent need for the antibiotic which will allow treatment of a wide range of bacterial parenteral infections so as to provide greater certainty of immediate effective treatment of parenteral bacterial infections including bacteria which have become resistant to one or more of the antibiotics currently used.
Acrolein is extremely damaging to body tissues due to its high reactivity. Pure polyacrolein, alone is not known to exhibit significant antimicrobial activity. However, a number of patents (Melrose et al. 1988; Melrose 1996; Melrose and Huxham 2000; Melrose et al. 2001; Staton and Melrose 2002; Melrose et al. 2003; Tilbrook 2005; Melrose 2009) disclose the preparation and uses of modified polyacroleins as antimicrobial agents in the gastrointestinal tract. Acrolein is an extremely reactive monomer and when polymerized, rapidly forms a high molecular weight intractable network. Normally, anionic polymerizations are conducted in a solvent free of water and provide rapid polymerizations to form high molecular weight polymers.
The prior art ascribes the antimicrobial activity of the modified polyacroleins to their chemically reactive carbonyl groups, which in the gastrointestinal tract, are stated to destructively react with protein of microbes' outer membranes. One of the perceived advantages of the polymers described in the prior art is that they cannot penetrate the gut wall so that their activity is confined to the gastrointestinal tract. Melrose 2009 describes a polyacrolein polymer which may be formed by base catalyzed polymerization of acrolein and/or its acetal with an alkanol. The polymers have the advantage of a reduced propensity to migrate through membranes.
U.S. Pat. No. 6,060,571 (Werle et al.) describes acrolein releasing polymers which release sufficient acrolein to provide activity as sanitizing agents in water systems. Such polymers are not suitable for use in vivo due to the toxicity of the significant levels of acrolein released in aqueous media.
We have now found that low molecular weight copolymers comprising an acrolein derived segment and polyalkylene glycol oligomer segment may be prepared so as to limit the molecular weight of the copolymer to no more than 1500 Daltons, preferably no more than 1000 Daltons. Further we have found that the low molecular weight copolymers provide potent antimicrobial activity for treatment of parenteral infections, without release of acrolein monomer. Indeed the activity has been found to be enhanced when compared with acrolein polymers of higher molecular weight.
The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge as at the priority date of any of the claims.